The long-term objective of this proposal is to understand the cellular and molecular mechanisms that underlie the development of chronic inflammatory bladder pain. Chronic inflammatory bladder pain as a result of Painful Bladder Syndrome (PBS) is a debilitating medical condition that affects women nine times more than men. PBS severely interferes with employment, social relationships and sexual activity. Estimated to effect anywhere from 3-12% of women in the U.S., the etiology is unknown. Furthermore, only a small percentage of patients with PBS respond to current available treatments. However, preliminary pharmacologic evidence from our lab indicates that activation of metabotropic glutamate receptor 5 (mGluR5) is important in inflammatory and non-inflammatory bladder pain. This proposal is designed to assess the role that mGluR5 plays in chronic inflammatory bladder pain. In mice with and without chronic bladder inflammation, systemic treatment with a specific mGluR5 antagonist reduces the pain-related response to bladder distention. Because mGluR5 is expressed throughout the central and peripheral nervous system, it is unknown whether the antagonist is acting on mGluR5 in the peripheral or central nervous system. Therefore, it is unknown whether peripheral and/or central expression of mGluR5 is important for the full expression of inflammatory bladder pain. There can be undesirable side effects of drugs that act on the central nervous system, knowing whether central or peripheral activation of mGluR5 is important in chronic inflammatory bladder pain will be valuable for future drug development. Furthermore, the molecular mechanisms through which mGluR5 activation plays a role in the expression of inflammatory bladder pain is unknown. We will address both of these issues through the experiments in this proposal. First, we will test whether central or peripheral expression of mGluR5 is necessary for full expression of inflammatory bladder pain. Second, we will address the molecular mechanisms underlying mGluR5-induced bladder hypersensitivity. The experiments in this proposal will provide critical insight into the role of both central and peripheral mGluR5 in inflammatory bladder pain and the molecular mechanisms through which mGluR5 activation results in hypersensitivity. The information gained from this proposal will directly guide both future bladder pain research and the development of reliable therapeutic interventions for the treatment of humans with chronic bladder pain. PUBLIC HEALTH RELEVANCE: The research described in this proposal will advance our understanding of chronic inflammatory bladder pain. The long-term goal of this proposal is to gain insight into the molecular and cellular mechanisms of chronic inflammatory bladder pain as well as the validation of molecular targets for the development of analgesics.